Lubricant coating and medical injection device comprising such a coating

ABSTRACT

The invention relates to a lubricant coating ( 5 ) for a medical injection device ( 1 ), comprising successively: —a bottom layer ( 50 ) in contact with the medical device surface ( 21 ) of the container to be lubricated, comprising a mixture of cross-linked and non-cross-linked poly-(dimethylsiloxane), —an intermediate layer ( 51 ) consisting essentially of oxidized poly-(dimethylsiloxane) and having a thickness comprised between 10 and 30 nm and, —a top layer ( 52 ) consisting essentially of non-cross-linked poly-(dimethylsiloxane) and having a thickness of at most 2 nm. The invention also relates to a medical injection device comprising such a lubricant coating, and a manufacturing process for said coating.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is the United States national phase of InternationalApplication No. PCT/EP2013/061007 filed May 29, 2013, and claimspriority to European Patent Application No. 12305592.3 filed May 29,2012, the disclosures of which are hereby incorporated in their entiretyby reference.

FIELD OF THE INVENTION

The invention relates to a lubricant coating, in particular for medicalinjection devices, a medical injection device comprising such alubricant coating, and a process for manufacturing such a lubricantcoating.

BACKGROUND OF THE INVENTION

Medical injection devices that comprise a sealing stopper in a glidingengagement within a container are widely used to deliver drug byinjection to a patient.

Such injection devices include syringes, cartridges and auto-injectors.

Many different types of injection devices have been designed foradministering medicines. Injection devices usually comprise a containerintended to receive the product to be injected and a plunger rodintended to move a stopper within the container so as to expel theproduct therefrom at the time of injection. Empty and pre-filleddisposable injection devices exist but prefilled devices are nowpreferred because they are more convenient and safer.

Such injection devices would be appropriate for containing newhigh-value drugs also commonly named “biotech” drugs that are currentlydeveloped and launched on the pharmaceutical market.

These biotech drugs can comprise for example biological elements such asproteins, peptides, DNA, RNA and the like, as well as sensitivecompounds.

A major constraint with such drugs is their sensitivity towards theirenvironment and therefore there is a need to find an appropriatecontainer able to maintain the integrity of the drugs when they arestored for a long time in injection devices.

Traditional injection devices comprise a container made of glass orplastic and a stopper made of rubber.

Optionally, coatings can be applied on the surface of the containerand/or on the surface of the stopper in order to improve the lubricationof the stopper inside the container.

But in some cases, it has been shown that such injection devices are notappropriate for long storage of high-value drugs due to the high andlong term interaction with their containers.

Indeed, it has been shown that some degradations of the drug(aggregation, denaturing, unfolding, etc. . . . ) occur with time,leading to the withdrawal of the prefilled device out of the market andtherefore leading to a high loss for pharmaceutical companies as well asleading to a risk for patients to be treated with degradedpharmaceutical drugs.

Therefore there is a need to have a prefilled injection device having amedical container compatible with biotech drugs, meaning a containerthat avoids any denaturing and/or aggregation of the drug after filling.

In addition, such prefilled injection devices should also have goodgliding properties i.e. a low gliding force to move the stopper withinthe container.

Moreover, if a coating is applied on the surface of the prefilledinjection device, the integrity of the coating has to be maintained fromthe deposition of the coating on the surface(s) of the medical deviceuntil the injection of the drug to the patient.

It means that any delaminating or breaking phenomena of the coating areto be avoided.

This is particularly the case for lubricant coatings that are commonlyused to enhance the gliding properties of the injection devices.

Finally, the integrity of the drug, the integrity of the lubricantcoating and the gliding properties of the prefilled device need to bemaintained over time i.e. to be stable for at least the shelf life ofthe prefilled injection device.

Some documents such as U.S. Pat. No. 5,338,312 and EP 0 201 915,describe an injection device having enhanced gliding properties by usinga lubricant coating that is cross-linked in order to immobilize thelayer on the surface of the container of the injection device.

However, such injection devices are not necessarily compatible withsensitive drugs such as biotech drugs and/or vaccines.

Further, these documents do not address the issue of providing a coatingthat would keep its integrity within time and that would not have anysignificant or adverse interaction with the drug contained inside theinjection device.

The document EP 1 060 031 describes a lubricated medical container thatexhibits good gliding properties as well as low protein adsorption onthe inner surface of the container.

Nevertheless, this document does not disclose any coating compatiblewith sensitive drugs such as vaccines and/or biotech drugs.

Indeed, as the coating described is not directed to be used withhigh-value drugs, even if the adsorption may be avoided, some denaturingof the drugs could occur.

This would be the case for example, with some polymers described in thisdocument such as polymers with phosphorylcholine groups orpoly-(2-hydroxyethyl methacrylate).

Additionally, this document does not disclose any information on acoating that keeps its integrity over time, after a long storage period.

However, the issue of storage is essential for prefilled syringes, asthe lubricant coating needs to be stable over time not only before thefilling of the drug in the injection device but also after the drug hasbeen introduced in the injection device.

Recently, it has been demonstrated that particles can appear in thepharmaceutical composition after the filling of the container, due tointeraction of the drug with the coating present on the inner wall ofthe container or on the surface of the stopper.

Generally speaking, silicone or silicone derivatives are often used aslubricant, and they have been identified as a main source of particlegeneration.

Indeed, specialists have observed that significant amounts of subvisibleparticles (i.e. particles having a size comprised between 0.1 μm and 100μm) accelerate protein aggregation and unfolding.

Furthermore, sub-visible particles consisting of silicone, proteinaggregates, or mixture of silicone with unfolded proteins and/orexcipients may be hazardous for patients: it is thus recommended thatthe level of particles in this size range be carefully controlled.

One can refer in this respect to “Overlooking Subvisible Particles inTherapeutic Protein Products: Gaps That May Compromise Product Quality”,by John F. Carpenter et al., Journal of Pharmaceutical Sciences, Vol.98, No. 4, April 2009.

These recommendations have been translated in more severe norms withregard to the maximum authorized particle level defined by the UnitedStates Pharmacopeia (USP 31 <788>) and the European Pharmacopeia (EP 6<2.9.19>).

These norms not only place a heavy burden onto the pharmaceuticalcompanies themselves but also onto the manufacturers of injectiondevices, since the release of particles from the containers into thepharmaceutical composition can occur and has to be avoided or at leastdramatically reduced.

A goal of the invention is thus to provide a lubricant coating thatexhibits a good compatibility with sensitive drugs stored inside acoated medical injection device for long time period in order to meetthe pharmacopeia norms with regard to the level of particles in thedrug, while still providing good performance with regard to the glidingof the stopper within the container of the medical injection device, andkeeping its integrity over time.

BRIEF DESCRIPTION OF THE INVENTION

An object of the invention is a lubricant coating for a medicalinjection device, comprising successively:

-   -   a bottom layer in contact with the medical device surface of the        container to be lubricated, comprising a mixture of cross-linked        and non-cross-linked poly-(dimethylsiloxane),    -   an intermediate layer consisting essentially of oxidized        poly-(dimethylsiloxane) and having a thickness comprised between        10 and 30 nm, said thickness being measured by        Time-Of-Flight-Secondary Ion Mass Spectrometry as described        herein, and,    -   a top layer consisting essentially of non-cross-linked        poly-(dimethylsiloxane) and having a thickness of at most 2 nm,        said thickness being measured by X-ray Photoelectron        Spectroscopy as described herein.

“Composition consisting essentially of” means a composition that cancontain, in addition to the components explicitly recited, only othercomponents which do not materially affect the essential characteristicsof the composition, such as minor amounts of impurities.

According to a preferred embodiment, the bottom layer is a gel.

Other advantageous features of the coating, taken separately or incombination, are the following:

-   -   said coating has a thickness comprised between 90 and 400 nm;    -   the thickness of the bottom layer is between 58 and 388 nm;    -   the formula of the oxidized poly-(dimethylsiloxane) of the        intermediate layer (51) is:        [SiO(CH₃)_(2-x)(OH)_(x)]_(n),

where x ranges from 0.2 to 1.5 and n is an integer;

-   -   preferably, x=0.75;    -   n ranges from 70 to 100;    -   the thickness of the intermediate layer is between 15 and 25 nm.

Another object of the invention is a medical injection device comprisinga barrel and a stopper in gliding engagement within the barrel,characterized in that the inner wall of the barrel is at least partiallycovered by a lubricant coating as described above.

The gliding force of the stopper within the barrel is advantageouslycomprised between 1 and 8 N, preferably between 3 and 6 N, said glidingforce being measured as described herein.

The barrel may be made of glass.

According to an embodiment, said medical device consists of a syringehaving an internal volume of 1 ml and a diameter of 6.35 mm.

The weight of the lubricant coating may then be between 0.1 and 0.4 mg.

The particle level generated inside the device when filled with asolution of a mixture of 10 g/L of Phosphate Buffered Saline and 2.13mg/L of Polysorbate 80 in Water for Injection and filtered with a 0.22microns filter, is preferably less than 2.11 particles per mm² ofcoating when measured by light obscuration method as described hereinand/or less than 10.56 particles per mm² of coating when measured byflow microscopy as described herein.

Another object of the invention is a process of manufacturing alubricant coating as described above.

Said process advantageously comprises the following steps:

-   -   depositing a layer of poly-(dimethylsiloxane) on a substrate,        the thickness of said layer being comprised between 90 and 400        nm, measured by reflectometry as described herein,    -   exposing said layer to an oxidizing plasma, so as to form said        lubricant coating by oxidizing and cross-linking at least part        of the poly-(dimethylsiloxane).

According to advantageous embodiments of this process, taken alone or incombination:

-   -   the viscosity of the deposited poly-(dimethylsiloxane) is        between 900 and 1200 cSt, preferably 1000 cSt at 25° C.;    -   said oxidizing plasma is carried out in an atmosphere comprising        oxygen and argon;    -   the atmosphere of said oxidizing plasma contains oxygen and        argon with respective partial pressures comprised between 15 and        30% for oxygen and between 85 and 70% for argon;    -   the duration of exposure is between 10 and 40 seconds;    -   the oxidizing plasma is generated by radio-frequency, with a        power ranging from 50 to 300 W, and under a vacuum in the range        1.33-13.3 Pa (10-100 mTorr) in absolute value.

BRIEF DESCRIPTION OF THE DRAWINGS

Other features and advantages of the invention will be apparent from thedetailed description that follows, based on the appended drawingswherein:

FIG. 1 is a schematic sectional view of a medical injection deviceaccording to one embodiment of the invention,

FIG. 2 shows a sectional view of a lubricant coating according to apreferred embodiment of the invention,

FIG. 3 shows the Time-Of-Flight-Secondary Ion Mass Spectrometry(TOF-SIMS) measurements for a lubricant coating according to anembodiment of the invention (graph (a)) and for apoly-(dimethylsiloxane) (PDMS) layer (graph (b)),

FIG. 4 shows optical microscopy images of a PDMS layer (image (a)) andof a lubricant coating according to an embodiment of the invention(image (b)) after manual scratching,

FIGS. 5A and 5B are schematic drawings illustrating the LightObscuration method (HIAC),

FIGS. 6A and 6B are schematic drawings illustrating the Micro-FlowImagine™ (MFI™) method,

FIG. 7 shows the particle level measured by MFI™ in a syringe containinga lubricant coating according to the invention (a) and a syringecontaining a PDMS layer (b),

FIG. 8 shows the particle level measured by HIAC in a syringe containinga lubricant coating according to the invention (a) and a syringecontaining a PDMS layer (b),

FIG. 9 shows the gliding force of a stopper within the barrel of asyringe containing a lubricant coating according to the invention (a)and a syringe containing a PDMS layer (b),

FIG. 10 shows the evolution of the stopper gliding force before andafter one month of ageing (T0/T1).

DETAILED DESCRIPTION OF EMBODIMENTS OF THE INVENTION

Referring to FIG. 1, the medical injection device 1 according to thepresent invention comprises a container, such as a barrel 2, and astopper 3 in gliding engagement within the barrel 2.

The barrel 2 of the injection device may be made of any kind of glass orplastic suitable for medical applications.

The stopper 3 may be made of any elastomeric material, e.g. rubber,butyl rubber, silicone rubber or a mixture.

The stopper 3 may be adapted to be connected for example to a plungerrod of a syringe or to a plunger rod of an injection pump, theconnection being done by any suitable connecting means, e.g. a threadedportion 31, etc.

The tip 20 of the barrel 2 opposed to the stopper 3 may be luer-type inorder to be connected to a needle hub, a cap or a catheter, or maycomprise a needle 4.

In the present invention, the inner wall 21 of the barrel 2 is coatedwith a lubricant coating 5.

This medical device may be a prefilled injection device, such assyringe, a cartridge or an auto-injector that may contain apharmaceutical composition 6 that can be a high-value drug, i.e. avaccine or a biotech drug.

The lubricant coating 5 present on the inner wall 21 of the medicaldevice can be represented as shown on FIG. 2. This figure shows asectional view of a lubricant coating according to a preferredembodiment of the invention.

The inner wall 21 may be planar, curved, or have any other geometry.

The lubricant coating 5 comprises a bottom layer 50 in direct contactwith the inner wall 21 of the barrel 2, an intermediate layer 51 and atop layer 52 in contact with the pharmaceutical composition 6 containedwithin the medical device.

The bottom layer 50 comprises a mixture of cross-linked andnon-cross-linked poly-(dimethylsiloxane), commonly named PDMS.

Preferably, said bottom layer has a gel structure, i.e. athree-dimensional solid network provided by the cross-linkedpoly-(dimethylsiloxane) that retains a liquid phase corresponding to thefree non-cross-linked poly-(dimethylsiloxane).

Above the bottom layer 50, the intermediate layer 51 consistsessentially of oxidized poly-(dimethylsiloxane) and has a thicknesscomprised between 10 and 30 nm.

Preferably, this oxidized PDMS is characterized by a higher ratio ofoxygen regarding PDMS, meaning an increase of around 4.5% below theusual rate of oxygen present in PDMS, as well as a smaller ratio ofcarbon, i.e. a decrease of around 4.5% below the usual rate of carbonpresent in PDMS.

Preferably, the chemical formula of the intermediate layer 51 mayadvantageously be:[SiO(CH₃)_(2-x)(OH)_(x)]_(n),

where x ranges from 0.2 to 1.5.

In a preferred embodiment, x ranges from 0.6 to 1 or more precisely, xis equal to 0.75.

Furthermore, as the measure of the degree of polymerization n can besometimes challenging due to the specific geometry of the medical deviceand the low quantity of material in the lubricant coating, the n valueis estimated to be comprised from 70 to 100 or more precisely, n isestimated to be around 85.

Above the intermediate layer 51, the lubricant coating 5 comprises a toplayer 52 consisting essentially of poly-(dimethylsiloxane) and having athickness of at most 2 nm.

Preferably, the top layer 52 shows neither cross-linkage nor oxidation,and its chemical composition is substantially similar to pure PDMS.

Said top layer 52 is thus in contact with a pharmaceutical composition 6contained in the medical device.

The thickness of the lubricant coating 5 can range from 50 to 1000 nm.According to a preferred embodiment, the thickness of the lubricantcoating 5 is comprised between 50 and 500 nm.

Due to the specific composition of these three different layers, thelubricant coating 5 according to the present invention generates a verylow level of particles in the pharmaceutical composition 6 whilemaintaining very good mechanical performances.

Indeed, there is a direct relationship between the number of particlesand the surface of the coating as the particles can be generated by theinteraction of the pharmaceutical composition 6 with the lubricantcoating 5.

Therefore, the larger the surface of the coating is, the higher theamount of particles will be.

It has been shown that with the coating according to an embodiment ofthe invention, the level of particles present in the pharmaceuticalcomposition is below 2.11 particles per mm² of lubricant coating surfacewhen measured by HIAC and below 10.56 particles per mm² of lubricantcoating surface when measured by MFI™.

As shown on FIG. 1 different particles can be generated over time when amedical injection device is filled with a pharmaceutical composition andkeep under storage condition. For example, silicone particles A (e.g.droplets) can be released from the coating present on the inner wall ofthe medical device into the pharmaceutical composition.

The particles can also be aggregates or denatured drugs (referred as Bon FIG. 1) that are present in the pharmaceutical composition and thathave been formed by the interaction of the pharmaceutical compositionwith silicone particles A and/or with the lubricant coating.

A third category of particles (referred to as C) can be released in thepharmaceutical solution due to the mechanical friction of the stopperalong the wall of the barrel.

With the lubricant coating 5 according to the invention, the level ofparticles generated by the lubricant coating is significantly reduced,which implies that the level of subvisible particles that may bereleased into the pharmaceutical composition or be in contact with thepharmaceutical composition during the life of the injection device isreduced.

As a consequence, the risk of aggregation of proteins in the solutionitself, due to the adsorption generated by the surface of the siliconedroplets, as well as the risk of adsorption of proteins at the surfaceof the barrel is significantly reduced.

Therefore, the pharmaceutical composition stored in the medicalinjection device remains stable over time as neither aggregation nordenaturing of the drugs due to potential interaction with the coatingpresent on the inner surface of the container occur.

Further, since silicone particles are likely to be released in a verysmall amount into the pharmaceutical composition, they do not generateany background noise that would be detrimental to the monitoring ofprotein aggregation. Additionally, as particles formed by silicone ordenatured drugs are believed to present toxicity when injected into aliving organism, the coating of the present invention leads to minimizethe risk of contamination of the patient.

The lubricant coating applied on the inner wall of a medical containerin accordance with the present invention also shows favorable mechanicalproperties. For example, no delaminating or break-up of the coatingoccurs under energetic movement (for example during transportation), aswell as under dramatic changes in temperature. Indeed, the coatingremains stable when applied on the inner wall of the container withoutany release of elements.

A further effect in accordance with an embodiment of the presentinvention is that the above-mentioned technical effects i.e. goodgliding properties and favorable mechanical properties, remain stableduring a long period of time, for example from 12 to 24 months or more.

This is particularly important when the medical container is filled witha pharmaceutical composition and is stored in different conditions andpositions, is transported over long distances and then finally used toinject the pharmaceutical composition into a patient after a long periodof storage.

Another advantage of an embodiment of the invention is that no furtherchemical species are introduced within the medical container, since thesingle chemical compound consists in a classic silicone oil, alreadyused and authorized for medical use that leads to lower the risk ofunpredictable side effects.

When expressed in term of particles per mm² of lubricant coatingsurface, the particle level generated by an embodiment of the inventionis below 2.11 particles/mm² if measured by HIAC or below 10.56particles/mm² if measured by MFI™. As a result, the obtained medicalinjection device fulfills the above mentioned requirements, i.e. a highcompatibility with vaccines and biotech drugs, good gliding performance,favorable mechanical properties and maintenance of these properties overa long period of time (e.g. 12 to 24 months).

If the amount of particles present in a container having a lubricantcoating according to the present invention is compared to the amount ofparticles present on a similar container having a pure silicone oilcoating, the above values correspond respectively to a reduction ofparticles of at least 70% when measured by HIAC, and of at least 90%when measured by MFI™.

The lubricant coating 5 is advantageously formed by deposition of alayer of poly-(dimethylsiloxane) on the inner wall 21 of the medicalinjection device, followed by the exposure of said layer to an oxidizingplasma.

The deposition may be accomplished by any suitable technique, e.g.spraying, dipping, spin coating, etc. in order to obtain a layerthickness comprised between 50 and 1000 nm, depending of the surface andthe type or material of medical injection device.

According to a preferred embodiment, the viscosity of the deposited PDMSis comprised between 900 and 1200 centistokes (cSt), preferably 1000cSt, at 25° C.

The plasma treatment is carried out in an oxidizing atmosphere.

According to a preferred embodiment, the atmosphere is a mixture of 15to 30% of oxygen and 85 to 70% of argon. Unless otherwise specified, thecomposition of the atmosphere of the plasma treatment is expressedherein in terms of respective partial pressures. More preferably, theatmosphere comprises 25% of oxygen and 75% of argon.

Generally speaking, plasma may be produced by different techniques suchas corona discharge, microwave, radio-frequency or any other convenientmethod. However, the present invention is manufactured by a, radiofrequency plasma treatment, i.e. with a frequency ranging from 10 to 20MHz, preferably from 11 to 14 MHz.

The power applied to generate the plasma may be comprised between 50 and300 W, preferably between 100 and 250 W.

The plasma treatment may be carried out at room temperature (i.e. 25°C.) and under a vacuum ranging from 1.33 to 13.3 Pa (10 to 100 mTorr) inabsolute value.

The exposure time is typically comprised between 10 to 40 seconds.

Of course, the above parameters depend on the plasma reactor geometry,the surface and volume of the medical device comprising the lubricantcoating, the arrangement of the devices inside the plasma reactor, thethickness of the lubricant layer, etc.

As a consequence, tiny changes in parameters can lead to a verydifferent coating and the skilled person may select the parameters ofthe plasma treatment in order to optimize the treatment depending on theequipment used as well as on the devices to be treated.

Plasma Treatment for 1 ml Long Glass Syringes

For a 1 ml long syringe having a glass barrel, the preferred conditionsof the plasma treatment (hereinafter designated by the term “1 ml longplasma treatment”) are:

-   -   plasma type: capacitively coupled plasma driven by a        radiofrequency power supply at 13.56 MHz;    -   treatment time: 30 s;    -   power: 200 W;    -   pressure: 8 Pa (0.06 Torr);    -   atmosphere: 15/75 sscm of O₂ and Ar respectively.

This treatment is applied to a syringe containing a lubricant coatinghaving a weight of 0.4 mg.

Structure of the Lubricant Coating

The oxidizing plasma has the effect of oxidizing and cross-linking atleast part of the poly-(dimethylsiloxane) deposited on the medicalinjection device surface, therefore forming a lubricant coatingaccording to the present invention.

Since the plasma treatment does not substantially modify the thicknessof the lubricant coating, the thickness of the deposited PDMS layer ischosen depending on the required thickness of the lubricant coating.

The effect of an oxidizing plasma on a PDMS layer has been partiallydescribed by H. Hillborg et al in “Hydrophobicity recovery ofpolydimethylsiloxane after exposure to corona discharge”, Polymer, Vol.39, No 10, pp. 1991-1998, 1998.

A film comprising PDMS with a thickness of 1.6 mm was formed on asubstrate and subjected to a corona discharge of 1.5 or 2.6 W during 20minutes to 200 hours.

It was shown that the resulting film had an oxidized surface in the formof a silica-like layer having a thickness from 8 to 10 nm, leading to areduction of the hydrophobicity of the film.

However, a recovery of the hydrophobicity was observed after some time.

Indeed, as explained in this document, some non-cross-linked PDMSsituated below the oxidized layer was able to migrate toward the surfaceof the film through cracks and fissures in the oxidized layer, due tothe brittleness of this oxidized layer.

Although the lubricant coating according to embodiments of the inventionis much thinner than the film formed by Hillborg et al, and theconditions of the plasma treatment are substantially different fromtheir corona discharge, it is believed that a similar phenomenonexplains the presence of the top layer 52 consisting of non-cross-linkedPDMS above the oxidized intermediate layer 51.

The thickness of the top layer 52 may vary with the treatment duration.

Indeed, said thickness is substantially null immediately after theexposure to the oxidizing plasma, and increases with time until reachinga thickness of about 2 nm.

The composition and structure of the bottom layer 50, intermediate layer51 and top layer 52 have been investigated in detail using severaltechniques.

Composition of Top and Intermediate Layers

The composition of the top and the intermediate layers in silicon,oxygen and carbon has been analyzed by X-ray Photoelectron Spectroscopy(XPS).

A Surface Science SSX-100 electron spectrometer was used for thisexperiment by using widths, areas and binding energies of Si (2p), O(1s) and C (1s).

The samples were tilted in order to achieve different analysis depthsand three angles were used (10, 35 and 60°) for allowing an analysis atdifferent depths, respectively about 2, 5 and 10 nm from the surface.

The samples were prepared as explained below.

Small samples of glass (about 0.4*0.4 cm) were cut from each glassbarrel before deposition of any coating. The samples were washed withwater to remove dust and dried. Then, the clean samples werere-assembled with adhesive tape to form the original barrel.

A first set of barrels was then coated with a lubricant coating 5according to the present invention: they were siliconized with 0.25 mgof silicone Dow Corning PDMS 1000 cSt before being stored during oneweek and then submitted to a plasma treatment with a frequency of 13.56MHz, a power of 200 μl, a vacuum of 1.33 Pa (10 mTorr) and a exposuretime of 30 seconds.

A second set of barrels was just siliconized with 0.25 mg of siliconeDow Corning PDMS 1000 cSt.

Thereafter, the pre-cut samples were disassembled and analyzedseparately.

% C % O % Si % O/% C PDMS 49.9 23.9 26.2 0.5 Top layer 52 45.4 22.6 32.00.5 (Angle 10° - 2 nm) Intermediate layer 51 40.5 32.6 26.9 0.8 (Angle35° - 5 nm) Intermediate layer 51 44.6 28.6 26.8 0.6 (Angle 60° - 10 nm)

The above table shows the results of the chemical composition and theoxidation ratio oxygen regarding carbon (% O/% C) of PDMS, the top layer52 and the intermediate layer 51 of the lubricant coating 5 present onthe different samples.

The top layer 52 has been analyzed at its maximum depth meaning at 2 nmfrom the top surface (i.e. from the pharmaceutical composition 6) andshows a percentage of oxygen substantially similar to the percentage ofoxygen present in PDMS, namely 22.6% and an oxidation ratio of 0.5. Thechemical composition and the oxidation ratio of the top layer 52 areadvantageously close or similar to the composition and oxidation ratioof PDMS, as this top layer is in direct contact with the stopper 3 andplays a key role to achieve good mechanical and gliding performances.

Indeed, PDMS is known to be a good lubricant with a low viscosity rateand good gliding performances.

The analysis of the intermediate layer 51, analyzed at two differentdepths 5 nm and 10 nm from the top surface shows that this layer 51 atleast partially oxidized: it presents a significant higher percentage ofoxygen, i.e. 28.6%, which is around 4.75% higher than PDMS and anoxidation ratio of at least 0.6

The presence of free PDMS chains at the surface of the treated samplesreveals that the oxidized layer 51 is porous and allows diffusion ormigration of unreacted silicone chains from the bottom layer 50 to thesurface.

This is consistent with contact angle measurements as it will be seenbelow.

Moreover, according to this analysis, it has been noticed that theoxidation ratio of the intermediate layer 51 is between 0.6 and 5,preferably between 0.8 and 2, or more precisely 1.4.

Furthermore, the average formula of the intermediate layer 51 mayadvantageously be as follows:[SiO(CH₃)_(2-x)(OH)_(x)]_(n),

where x ranges from 0.2 to 1.5.

In a preferred embodiment, x ranges from 0.6 to 1 or more precisely, xis equal to 0.75.

Furthermore, as the measure of the degree of polymerization n can besometimes challenging due to the specific geometry of the medical deviceand the low quantity of material in the lubricant coating, this n valueis estimated to be comprised from 70 to 100 or more precisely, n isestimated to be around 85.

This intermediate layer 51 plays a key role to limit the generation ofparticles in the pharmaceutical composition.

Indeed, this intermediate layer acts as a brittle barrier to preventdirect interaction between the pharmaceutical composition and the bottomlayer which essentially consists of free PDMS.

Therefore, free PDMS cannot diffuse massively into the pharmaceuticalcomposition.

Only a limited amount of free PDMS can migrate through this intermediatelayer to form the thin top layer 52.

Then, this top layer 52 remains strongly linked to the intermediatelayer 51 by intermolecular bonds, and does not generate high amount ofparticles.

Moreover, mechanical properties are enhanced since this intermediatelayer 51, contributes substantially to the lubricant coating rigidity.

As this oxidized layer has a glass-like structure, the hydrophobicity ofthe lubricant coating surface is also limited, hence enhancing itscompatibility with biotech drugs and vaccines.

Finally, this brittle intermediate layer can be easily deformed by themovement of a stopper inside the coated barrel, which allows sufficientlubrication for preserving the gliding properties.

Thickness of the Intermediate Layer

The thickness of the oxidized intermediate layer has been measured byTOF-SIMS technique: this technique performs the erosion of a surface byan ion-beam and the secondary ions produced during the erosion processare analyzed. TOF-SIMS profiles have been performed at differentlocations on the barrel of a 1 ml long glass syringe on samples coatedwith a lubricant coating 5 or samples coated with PDMS.

A Bi₃ analytical source at 25 kV was used together with a Cs abrasionsource at 500 V and the pressure in the analytical chamber was less than5×10⁻⁹ Torr.

The analysis has been carried out from the coating surface towards thethickness of the glass barrel.

To that end, samples were prepared as follows.

Small samples of glass (about 0.4*0.4 cm) were cut from each glassbarrel before deposition of any coating. The samples were washed withwater to remove dust and dried. Then, the clean samples werere-assembled with adhesive tape to form the original barrel.

A first set of barrels was then coated with a lubricant coatingaccording to the present invention: they were siliconized with 0.25 mgof silicone Dow Corning PDMS 1000 cSt before being stored during oneweek and then submitted to a plasma treatment with a frequency of 13.56MHz, a power of 200 W, a vacuum of 1.33 Pa (10 mTorr) and a exposuretime of 30 seconds.

A second set of barrels was only siliconized with 0.25 mg of siliconeDow Corning PDMS 1000 cSt.

Thereafter, the pre-cut samples were disassembled and analyzedseparately.

As the TOF-SIMS techniques gives a quantity of secondary ions as afunction of an erosion time, a calibration was realized in order tocorrelate the erosion time with the coating thickness. To that end, thehypothesis was made that the erosion time of a 1000 cSt PDMS layer andthe one of the lubricant coating 5 were substantially similar.

A calibration sample was performed by using a PDMS layer deposited byspin coating on a glass surface.

The layer thickness of this calibration sample was measured byellipsometry and the erosion time for the whole layer was measured byTOF SIMS. It has been found that 43.2 seconds of erosion time areequivalent to 10 nm of PDMS.

FIG. 3 shows the results of the TOF SIMS measurements carried out on thelubricant coating 5 (graph (a)) and a PDMS layer (graph (b)). This FIG.3 represents the intensity of the secondary ions SiO₂ ⁻ and O₂ ⁻depending on the thickness of the layer (from the top surface in contactwith the pharmaceutical solution 6 to the bottom surface in contact withthe barrel inner wall 21).

A peak with a maximum near 5 nm can be seen on graph (a) for SiO₂ ⁻ andO₂ ⁻. This means that the intermediate layer is highly oxidized. On thecontrary, no peak can be seen on the graph (b) for the same secondaryions, corresponding to a PDMS layer.

According to these data, it can be concluded that the thickness of theintermediate layer 51 is comprised between 10 and 30 nm, preferablybetween 15 and 25 nm. These values are significant as a thinnerintermediate layer (below 10 nm) would not significantly prevent thegeneration of particles into the pharmaceutical solution while a thickerlayer (higher than 30 nm) could lose its mechanical properties anddemonstrate poor gliding performances.

Thickness of the Lubricant Coating

The thickness of the lubricant coating according to the presentinvention has been measured by reflectometry with a RapID equipment(namely a Silicone Layer Explorer Apparatus) and compared to a PDMSlayer.

Prior to the measurements, a calibration of the apparatus was requiredon a bare glass barrel (i.e. without any silicone), with a focus allalong the barrel length.

Each coating, either a PDMS layer or a coating according to the presentinvention, has been deposited on a 1 ml long bare glass barrel. Thethicknesses were compared and correlated with the particle levelgenerated, the mechanical performances and the mechanical properties.

It has been found that a layer thickness between 50 and 500 nm, moreprecisely between 90 and 400 nm was optimal to fulfill theserequirements with such syringe.

In this embodiment, the average thickness of the lubricant coatingthickness was found to be 150 nm.

Finally, it has been shown that the coating thickness is not modifiedduring the coating formation.

Wettability of the Lubricant Coating Surface

The wettability of the surfaces has been studied with a goniometer andWater For Injection (WFI).

The measurements of water angles were performed on lubricant coatingsaccording to the present invention after 3 days and 7 days of storage atroom temperature, in order to analyze the evolution of their hydrophobicproperties over time.

The table below summarizes the values of water angles obtained from thisexperiment by comparison with values obtained with a 1000 cSt PDMSlayer.

Sample Water angle with pure water PDMS 100-110° Lubricant coating 527-30° (3 days after treatment) Lubricant coating 5 50-54° (7 days aftertreatment)

The first line of the table shows a very high water angle between 100and 110° for PDMS, which demonstrates that this silicone oil is veryhydrophobic.

After manufacturing and a short storage time (3 days in thisexperiment), the lubricant coating 5 showed a very low water angle valuemeaning that its surface is very hydrophilic.

After a longer storage time (7 days from the treatment), an increase ofthe water angle is observed, corresponding to a hydrophobicity recoveryof the surface of the lubricant coating 5. It is then assumed that atiny quantity of PDMS is able to flow from the gelified bottom layer 50through the porous intermediate layer 51, therefore forming the toplayer 52.

As a result, after a short storage time (around one week), the lubricantcoating 5 as described above is definitely formed and presents amoderate hydrophilic surface, which allows for reduction of theinteraction with biotech drugs such as proteins and then limitation ofthe aggregation and denaturing phenomena.

Gel Structure of the Bottom Layer

The gel structure of the bottom layer 50 has been demonstrated byforming a scratch in the lubricant coating and by observing the behaviorof the resulting lubricant coating by optical microscopy with ×20magnification.

FIG. 4 shows the images obtained after a manual scratch of a PDMS layer(picture (a)) and manual scratch of the lubricant coating according tothe invention (picture (b)), both layers having the same thickness.

On picture (a), the scratch was not visible since the standard PDMSlayer has a viscous liquid structure, which allows the naturalrearrangement of the layer which leads to the disappearance of thescratch.

By contrast, a scratch made on the lubricant coating 5 (shown by thearrow on picture (b)) remained visible over time. This demonstrated thatthe lubricant coating 5 is a stable and solid coating due to thepresence of its gel bottom layer 50.

As no additional elements have been added during the manufacturingprocess, this gel bottom layer 50 can be analyzed as a network made ofsolid cross-linked PDMS and liquid PDMS.

The top and intermediate layers (51, 52) have a global thickness of atmost 32 nm, while the optimal total thickness of the coating for a 1 mllong syringe is at least 90 nm.

The thickness of the bottom layer 50 is inferred from the differencebetween the total thickness and the thickness of top and intermediatelayers.

Therefore the thickness of the bottom layer 50 is at least 58 nm, up to388 nm: this layer is the thicker layer of the coating.

The liquid PDMS within the gel network allows the formation of the toplayer 52, and therefore provides sufficient gliding properties.

The bottom layer 50 also prevents the release of silicone particles intothe pharmaceutical composition 6 by trapping most of the liquid PDMSinto the solid gel network.

Moreover, this bottom layer 50 is in direct contact with the inner wall21 of the barrel 2, and is therefore essential for mechanicalproperties.

Indeed, its gel structure prevents delamination of the lubricant coatingi.e. detachment from the inner wall surface, as well as break-up of thebrittle intermediate layer, that should occur upon energetic movementduring transportation or dramatic temperature change.

Particles Measurement (HiAc and MFI™)

The advantages of the lubricant coating according to embodiments of theinvention have also been demonstrated by the measurement of the level ofparticles in a solution contained in the medical injection device 1 andby the measurement of the gliding force of the stopper 3 within thebarrel 2 as it will be described below.

To measure the level of particles generated by the lubricant coating 5,a syringe 1 with a coating 5 according to the present invention wasfilled with a solution and the level of particles released in saidsolution was measured.

Said solution was a mixture of 10 g/L of Phosphate Buffered Saline and2.13 mg/L of Polysorbate 80 (e.g. Tween™ 80) filtered with a 0.22microns filter (e.g. Stericup™ filter).

The Phosphate Buffer Saline was purchased from Sigma Aldrich underreference P4417. One tablet dissolved in 200 ml of deionized wateryields 0.01 M phosphate buffer, 0.0027 M potassium chloride and 0.137 Msodium chloride, with a pH of 7.4 at 25° C.

After 2 hours of storage, the solution was introduced in different 1 mllong glass barrels.

Once the barrels were closed, the filled syringes were stirred during 48h before measuring the particle level.

Different methods and equipments may be used depending on the size ofthe particles to be detected and quantified.

In this case, the particles to be analyzed have a size between 1 μm to100 μm, preferably between 1 μm and 10 μm. They are usually detected byoptical devices and are called “subvisible particles” to the contrary ofthe so-called “visible particles” that have a size above 100 μm and canbe seen with a human eye.

For such subvisible particle sizes, the most suitable counting methodsare Light Obscuration (LO) or Micro Flow Imaging (MFI™), both of thesetechnologies being described in detail below.

Light obscuration is routinely used to detect and measure subvisibleparticles present in parenteral solutions i.e. solutions to be injectedin a living body.

As illustrated on FIG. 5B, when a particle P transits the measurementzone MZ in the direction of the arrow, it obscures (shadow S) an opticalbeam (e.g. generated by a light source L such as a laser diode with awavelength of 680 nm), which results in a change in signal strength at adetector D. This signal change is then equated to the diameter of anequivalent spherical particle based on a calibration curve created usingpolystyrene spheres with known diameters.

Devices based on this technique are sold under the brand HIAC by HachLange, for example.

Advantages of such light obscuration devices are that they are easy touse, automated and fast. The measured particles size range with suchdevices is typically comprised between 2 and 400 μm.

To provide accuracy, the device has to be used with a large volume ofsolution i.e. more than 3 ml, which is greater than the volume of asmall size syringe. This implies that 1 to 3 ml containers cannot beanalyzed one by one.

Therefore, as illustrated on FIG. 5A, several medical containers 1 (onlyone is shown in the figure) have to be flushed in an intermediate largercontainer 60 (e.g. a beaker) and the content of said intermediatecontainer 60 is then analyzed with the light obscuration device. Forconducting the analysis, the HIAC equipment was first cleaned with amixture of Water For Injection (WFI) and isopropanol alcohol (50/50proportion), then with WFI. All the glasswares used were also cleanedwith WFI in order to reduce the concentration of particles having a sizeof 10 μm under 1 particle/ml.

Then, the pharmacopeia norms have been applied on the above-describedsolution flushed from the containers. This means that the stopper wasmoved into the barrel towards the distal direction in order to eject thesolution through the nozzle of the medical container into theintermediate container 60.

The analysis of the samples according to the present invention consistedin four runs of at least 3 ml: the first run was used for cleaning andthen discarded, while the three following runs were used for themeasures. Then 3 ml of WFI were used for washing.

In the case of 1 ml medical container, several devices have been flushedinto a common recipient 60 in order to obtain the required analysisvolume.

A second technique used for particle measurement is Micro-Flow Imagine™(MFI™). This is a flow microscopy method which operates by capturingimages of particles in a flowing stream. For example, the equipment MFI™DPA4200 sold by Brightwell Technologies can be used.

As illustrated in FIG. 6B, a solution to analyze is pumped from acontainer and goes through a flow cell FC where it is enlighten by alight L.

A camera C acquires several pictures of a small zone MZ of the flow cellFC with a known frame rate and different magnification set-points.

Each picture is automatically compared with a calibrated background, adifference in pixel contrast revealing a particle P.

The detected particle is then digitally imaged to obtain supplementarycharacteristics (size, shape, etc.).

Due to particle imaging, an advantage of this device is that itdifferentiates an air bubble from a silicone oil droplet. Moreover, itis also possible to build a particle database including count, size,transparency and shape parameters in order to analyze particle sizedistributions and isolate subpopulations using any measured parameters.

The measured particles size range is typically between 1 and 100 μm.

The operating protocol was the following.

First, the flow cell integrity was checked to ensure accuracy of themeasurements.

Then, the cleanliness of the flow cell and the tubing was controlledwith a blank run performed with WFI (the particle number has to be below100 particles/ml).

A run with certified beads (e.g. with a size of 5 or 10 μm and with aconcentration of 3000 particles/ml) could also be carried out for thecalibration.

The measurement analysis of the samples according to the presentinvention consisted in 0.5 ml runs separated by 0.2 ml washings.

Unlike the analysis protocol performed with Light Obscuration, single 1ml syringes were analyzed in this case.

Indeed, as shown on FIG. 6A, the stopper 3 of each syringe to analyzewas removed and 0.5 ml of solution was taken from the syringe barrel 2to be introduced into the equipment.

A rinsing step was performed between each analysis, such steps beingcrucial for measurement accuracy.

FIG. 7 shows the particle level measured by flow microscopy in 1 ml longsyringes coated with a lubricant coating according to an embodiment ofthe invention, obtained by the above-defined “1 ml long plasmatreatment” (value (a)) and in 1 ml long syringes siliconized with PDMS(value (b)).

This value (b), obtained for a PDMS layer, was around 80000particles/ml.

In comparison, the value (a) obtained for the lubricant coating 5 wasbelow 4800 particles/ml which is more than 14 times less.

In other words, the particle level generated by a lubricant coating 5according to the present invention represents around 6% of the particlelevel generated by a PDMS coating, when measured by MFI™.

Similarly, FIG. 8 shows the particle level measured by HIAC in a 1 mllong glass syringe coated with a lubricant coating 5 obtained by theabove-defined “1 ml long plasma treatment” (value (a)) according to anembodiment of the invention and in a syringe coated with PDMS (value(b)).

The average particle level of a coating according to the invention is of1500 particles/ml (value (a)) and thus very low in comparison to the8500 particles/ml obtained from a PDMS coating, more precisely around 71times less.

In other words, the particle level generated by a lubricant coating 5according to the present invention represents around 17% of the particlelevel generated by a PDMS coating when measured by HIAC.

As particles are generated by the surface of a coating, particle valuescan be expressed by number per surface unit, i.e. particles per mm². Inthis case, the particle level generated by a lubricant coating 5 is lessthan 2.11 particles per mm² of coating when measured by HIAC LightObscuration method and less than 10.56 particles per mm² of coating whenmeasured by flow microscopy.

The difference between the particle level measured by HIAC and by MFI™is explained by the different sizes of particles measured by the twoapparatus: the HIAC apparatus measures particle sizes ranging from 2 to400 μm while the MFI™ measures particle sizes ranging from 1 to 100 μm.Moreover, small sized particles are generated in higher quantities by aPDMS coating, while big sized particles are generated in smaller amount.

As a result, the reduction of the particle level provided by a lubricantcoating 5 versus a PDMS coating is more significant when smaller sizedparticles are considered, than with the MFI™ technique.

To conclude, this coating shows both with HIAC and MFI™ a very highimprovement in terms of particle level in comparison to a PDMS coating.This allows the reduction of toxicity for patients while substantiallygives an increase in the stability for high value drugs stored in amedical container. Indeed, a lubricant coating emitting a low level ofparticles in the stored pharmaceutical composition prevents denaturationand degradation of this composition.

Gliding Force of the Stopper within the Barrel

In order to evaluate the gliding force of a stopper into a lubricatedbarrel, an empty 1 ml long glass syringe closed by a Daikyo Flurotec®stopper was connected to a traction-compression bench (Lloyd LRX Plus)for inducing the gliding of the stopper within the container.

The bench was used for compression at a speed of 380 mm/min with nopreload and the reference used was similar syringes lubricated with aPDMS coating with similar thickness.

FIG. 9 shows the gliding force of the stopper within a barrel lubricatedwith the lubricant coating according to an embodiment of the invention,obtained by the above-defined “1 ml long plasma treatment” (a) and abarrel lubricated with a PDMS coating (b).

This graph shows that the gliding force of a stopper in a syringe barrelcomprising the lubricant coating is around 3 N higher than the glidingforce of a stopper in a syringe barrel having a PDMS coating.

However, the average gliding force remains around 5 N and below 8 N,which is a suitable range for syringe applications.

More precisely, the gliding force obtained with syringes lubricated witha lubricant coating 5 was in the range of 3 to 6 N.

Thus, a lubricant coating 5 according to the present invention providesa low particle level into the pharmaceutical composition, a very goodcompatibility with vaccines and biotech drugs and good mechanicalproperties, while preserving an acceptable gliding force.

Then, in order to estimate the behavior of the coating over time,measurement of the gliding forces was performed on 1 ml long syringeslubricated with a lubricant coating according to the present invention,obtained by the above-defined “1 ml long plasma treatment”, directlyafter manufacturing, and after 1 month of storage under 40° C. and 75%of relative humidity.

In parallel, a visual check was performed to ensure that no delaminatingor break-up occurred during the one month period.

The result of this experiment can be shown on FIG. 10 where the glidingforce after a 1-month storage “T1” (on the left) is essentially similarto the gliding force measured without a storage period “T0” (on theright).

It can thus be concluded, from this experiment, that the lubricantcoating specific composition enables to maintain its advantages overtime which is particularly interesting in the field of prefilled medicalcontainers.

Indeed, as prefilled medical containers are stored in pharmacy,warehouse or hospitals for a period ranging from 12 to 24 months or morebefore being used by medical staff, a lubricant coating according to thepresent invention ensures a constant level of gliding whatever thestorage period.

Finally, it should be noted that the lubricant coating 5 shows a lowrisk of unpredictable side effects as it is based on classic PDMSsilicone oil which has been submitted to extensive toxicology tests andis currently authorized for medical use.

While specific embodiments of the invention are described with referenceto the figures, those skilled in the art may make modifications andalterations to such embodiments without departing from the scope andspirit of the invention. Accordingly, the above detailed description isintended to be illustrative rather than restrictive. The invention isdefined by the appended claims, and all changes to the invention thatfall within the meaning and range of equivalency of the claims are to beembraced within their scope.

The invention claimed is:
 1. A lubricant coating for a medical device,comprising: a bottom layer in contact with a surface of the medicaldevice to be lubricated, comprising a mixture of cross-linked andnon-cross-linked poly-(dimethylsiloxane); an intermediate layerconsisting essentially of oxidized poly-(dimethylsiloxane) and having athickness between 10 and 30 nm; and a top layer consisting essentiallyof non-cross-linked poly-(dimethylsiloxane) and having a thickness of atmost 2 nm.
 2. The lubricant coating according to claim 1, wherein thebottom layer is a gel.
 3. The lubricant coating according to claim 1,having a thickness between 90 and 400 nm.
 4. The lubricant coatingaccording to claim 1, wherein the thickness of the bottom layer isbetween 58 and 388 nm.
 5. The lubricant coating according to claim 1,wherein the formula of the oxidized poly-(dimethylsiloxane) of theintermediate layer is:[SiO(CH₃)_(2-x)(OH)_(x)]_(n), where x ranges from 0.2 to 1.5 and n is aninteger.
 6. The lubricant coating according to claim 5, wherein x=0.75.7. The lubricant coating according to claim 5, wherein n ranges from 70to
 100. 8. The lubricant coating according to claim 1, wherein thethickness of the intermediate layer is between 15 and 25 nm.
 9. Aprocess for manufacturing a lubricant coating, comprising: depositing alayer of poly-(dimethylsiloxane) on a substrate, the thickness of saidlayer being between 90 and 400 nm; and exposing said layer to anoxidizing plasma, so as to form said lubricant coating by oxidizing andcross-linking at least part of the poly-(dimethylsiloxane), wherein saidoxidizing plasma is carried out in an atmosphere comprising oxygen andargon, wherein the atmosphere of said oxidizing plasma contains oxygenand argon with respective partial pressures between 15 and 30% foroxygen and between 70 and 85% for argon, and wherein the step ofexposing is an exposure between 10 and 40 seconds.
 10. The processaccording to claim 9, wherein a viscosity of the depositedpoly-(dimethylsiloxane) is between 900 and 1200 cSt at 25° C.
 11. Theprocess according to claim 9, wherein the oxidizing plasma is generatedby radio-frequency, with a power ranging from 50 to 300 W, and under avacuum in the range 1.33-13.3 Pa (10-100 mTorr) in absolute value.